Results: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89−1.07) for hypertension, 0.97 (95% CI: 0.88−1.08) for hyperlipidemia, 1.01 (95% CI: 0.89−1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08−1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68−0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22−1.52) and 1.08 (95% CI: 0.90−1.29), respectively.

Conclusions: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE.

Introduction

Each year, > 500 000 individuals in the United States and European Union die from venous thromboembolism (VTE).1,2 Among VTE survivors, 50% have long-term complications.1,2 VTE, consisting of deep-vein thrombosis (DVT) or pulmonary embolism (PE), is clinically defined as either provoked or unprovoked. Provoked events are preceded by triggering generally transient risk factors such as immobilization, surgery, major trauma, or cancer3; ≈50% of VTEs occur in the absence of any risk factors and are classified as unprovoked.4 Apart from the aforementioned provoking factors, older age, family history of VTE, certain genetic variants, oral contraceptive use, and obesity are also known major VTE risk factors.

In contrast, arterial thromboembolism, comprising coronary heart disease, stroke, and peripheral artery disease, mainly occurs with atherosclerosis, which is primarily driven by the major modifiable traditional cardiovascular disease (CVD) risk factors such as hypertension, hyperlipidemia, diabetes, and smoking.5 The traditional CVD risk factors and VTE share some common lifestyle risk factors such as physical inactivity and obesity. Nevertheless, VTE and CVD have historically been viewed as 2 different diseases with distinct risk factors.6

In the last decade, several studies on the associations of CVD risk factors with VTE risk have been conducted with inconclusive results.6–16 In 2008, a meta-analysis showed positive associations for hypertension, diabetes, hyperlipidemia, and smoking with VTE incidence.8 However, this meta-analysis did not adjust for important confounders such as age and body mass index and included primarily studies with case-control design and nonvalidated outcomes. To obtain robust evidence with minimal bias, we performed an individual-level data meta-analysis of prospective studies in which traditional CVD risk factors were measured and VTE events validated.

Methods

Study Selection Criteria

Eligible studies had to be prospective cohorts or clinical trials with measured CVD risk factors and validated VTE events. A PubMed search was performed on October 21, 2014, with terms for each traditional CVD risk factor and VTE excluding newborns and infants (search strategy described in the online-only Data Supplement). Results were restricted to English language, humans, and a publication date after January 1, 1980 (because reliable diagnostic modalities for VTE were not widely available before 1980). Of 3192 publications (Figure 1) screened by reading the titles and abstracts, 46 studies were selected for full-text review, with 11 meeting eligibility criteria. Another 2 unpublished cohort studies were identified by personal contacts. Of the 13 studies that met the inclusion criteria of being prospective studies with data on measured CVD risk factors and validated VTE events, 2 were unable to provide data,17,18 and 2 did not reply to our invitation.19,20 Therefore, 9 studies were included in the meta-analysis.13–16,21–25

Outcome Variables Definitions

Only objectively verified, symptomatic, and validated VTE events were included. DVT was confirmed by duplex ultrasound or venography and PE by ventilation/perfusion lung scanning, angiography, spiral computed tomography, or autopsy. Patients with PE and concurrent DVT were included in the PE group. We defined provoked or unprovoked VTE based on each study’s definition. Major trauma, surgery, significant immobilization, or active cancer in the preceding 3 months were the main determinants for classifying VTE as provoked. Some cohorts included additional exposures to define provoked VTE, such as the use of oral contraceptives or hormone therapy, pregnancy, long-distance travel, active infectious disease, acute myocardial infarction, paresis/paralysis of the leg, and heart failure (online-only Data Supplement). In each study, in the absence of the study-defined provoking factors, VTE was classified as unprovoked.

Exposure Variables Definitions

Risk factor definitions were harmonized across studies. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medication. Diabetes mellitus was defined as fasting glucose concentration ≥7.0 mmol/L (≥126 mg/dL), nonfasting glucose concentration ≥11.1 mmol/L (≥200 mg/dL), or use of glucose-lowering drugs or self-reported diabetes mellitus. Hyperlipidemia was defined as total cholesterol ≥5.0 mmol/L (≥193 mg/dL) in patients with a history of CVD and ≥6.0 mmol/L (≥232 mg/dL) in patients without a history of CVD, or use of lipid-lowering medication. History of CVD was defined as previous myocardial infarction, coronary revascularization, stroke, or peripheral artery disease objectively verified by diagnostic modalities, revascularization, or amputations due to ischemia. Smoking was dichotomized as self-reported current smoking versus former or never smoking combined and as former smoking versus never smoking. Body mass index (BMI) was calculated as body weight in kilograms divided by squared height in meters.

Statistical Analysis

Analyses were performed in 2 stages. First, each study analyzed the data with a centrally developed statistical code. The study-specific estimates and contrasts were shared with the study coordinator (B.K.M.) to perform the meta-analysis. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) of overall VTE and VTE subtypes. We tested 3 models: (1) unadjusted; (2) age, sex, and BMI (continuous) adjusted; and (3) fully adjusted. The fully adjusted model included age, sex, race, BMI (continuous), history of CVD, history of VTE, hypertension, diabetes mellitus, hypercholesterolemia, and current and former smoking. If 1 or more of the variables listed for the fully adjusted model were not ascertained in a study, that specific variable was dropped from the list of the fully adjusted model variables for that study. To adjust for trial arms or multiple subcohorts (eg, Framingham Heart Study), Cox models with strata option were fit, with the strata variable representing the randomization status or subcohorts.

In addition to categorical analyses, systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse pressure, total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides were analyzed continuously using restricted cubic splines. The blood pressure models were adjusted for age, sex, BMI (continuous), history of CVD, and antihypertensive drugs. Similarly, lipid measures were adjusted for age, sex, BMI (continuous), history of CVD, and use of lipid-lowering medication. Knots and reference values for these variables were prespecified and partially based on the distribution of these variables in the REGARDS (Reasons for Geographic and Racial Differences in Stroke study) and PREVEND (Prevention of Renal and Vascular Endstage Disease) studies to avoid extreme knots outside the data range. The same knots and reference values were used across all studies.

In sensitivity analysis, the associations of the exposure variables with the overall VTE and subtypes of VTE were assessed for the first 5 years of follow-up to assess whether the long follow-up available in most studies could have diluted the exposure-outcome risk associations.

In the second stage, the obtained estimates from individual studies were meta-analyzed using random-effect meta-analysis. If a study had 0 events in a certain spline section, then the estimate of that study for that particular spline section was dropped from the meta-analysis. Heterogeneity of the pooled estimates was assessed using the χ2 test for heterogeneity and the I2 statistic. Potential sources of heterogeneity were explored by meta-regression analysis. In all analyses, a P value of <0.05 was considered statistically significant. All analyses were conducted using Stata 12.2 (www.stata.com), and some figures were constructed with R version 2.14.1.

Results

Baseline characteristics of the 9 studies are shown in Table 1. Eight studies were community-based prospective cohort studies, and 1 study consisted of 2 clinical trials including only women. Of the 244 865 participants in the analysis, 4910 developed VTE during the mean follow-up ranging from 4.7 to 19.7 years per study. Of 4910 VTE events, 36% occurred within the first 5 years of follow-up. Overall, 44% of the VTE events were classified as unprovoked and 44% as PE with or without concurrent DVT (Table 1). Race was not considered as a covariate in the Framingham Heart Study and European cohorts becausee ≥95% of participants in these studies were white. Unavailable data included prior history of CVD in 1 study, hyperlipidemia and lipid measures in 1 study, and prebaseline history of VTE in 5 studies. Current smoking was available in all studies, whereas in 2 studies former smoking status was not available. The proportion of missing values was <1% for the majority of the variables (online-only Data Supplement Table I).

Baseline Characteristics and VTE Events During Follow-Up of Individual Studies

Risk of VTE Outcomes During Total Follow-Up

Pooled estimates of associations of categorical CVD risk factors with VTE are shown in Figure 2. Except for current smoking, all variables showed clear positive associations with VTE in the unadjusted models. However, adjustment for age, sex, and BMI resulted in the elimination of VTE risk associations for hypertension (HR=0.98 [95% confidence interval (CI): 0.89−1.07]), hyperlipidemia (HR=0.97 [95% CI: 0.88−1.08]), diabetes mellitus (HR=1.01 [95% CI: 0.89−1.15]), and former smoking (HR=0.99 [95% CI: 0.93−1.06]). Current smoking (HR=1.19 [95% CI: 1.08−1.32]) was positively associated with overall VTE in this age-, sex-, and BMI-adjusted model. Estimates remained largely unchanged in fully adjusted models. Heterogeneity across studies tended to be moderate to high for the crude associations (I2 values ranging from 50% to 92%) but low in the adjusted models, with an exception for current smoking (I2=51%). Using meta-regression, of the study-level variables shown in Table 1, none of these explained the heterogeneity observed for current smoking in the fully adjusted overall VTE model. Results were generally similar for unprovoked versus provoked VTE and PE versus DVT (online-only Data Supplement Figures I–IV). Exceptions were that in the fully adjusted models, current smoking was only associated with provoked (HR=1.36 [95% CI: 1.22−1.52], I2=0%) and not with unprovoked (HR=1.08 [95% CI: 0.90−1.29], I2=42%) VTE. Similarly, former smoking was only associated with provoked (HR=1.11 [95% CI: 1.00−1.23], I2=0%) but not unprovoked (HR=1.01 [95% CI: 0.89−1.16], I2=21%) VTE.

Pooled hazard ratios of overall venous thromboembolism (VTE) according to blood pressure measurements for systolic pressure (A), diastolic pressure(B), pulse pressure(C), and mean arterial pressure (D). Estimates are adjusted for age, sex, body mass index (BMI) (continuous), history of cardiovascular disease, and antihypertensive medication use. The black line and error bars depict hazard ratios and 95% confidence intervals, with the gray dots indicating statistical significance (P<0.05) and the black diamond the reference value. The heights of the bars shown with the gray lines at the bottom of each graph depict the number of participants at each spline section, and the widths of these bars correspond to the splines range.

Pooled hazard ratios of overall venous thromboembolism (VTE) according to lipid measurements for total cholesterol (A), low-density lipoproteins (B), high-density lipoproteins (C), and triglycerides (D) levels. Estimates are adjusted for age, sex, body mass index (BMI) (continuous), history of cardiovascular disease, and lipid-lowering medication use. The black line and error bars depict hazard rations and 95% confidence intervals, with the gray dots indicating statistical significance (P<0.05) and the black diamond the reference value. The heights of the bars shown with the gray lines at the bottom of each graph depict the number of participants at each spline section, and the widths of these bars correspond to the splines range.

Sensitivity Analyses on the Risk of VTE During the First 5 Years of Follow-Up

Compared with the total follow-up, the risk associations in the first 5 years of follow-up were generally comparable, except CIs were slightly wider because of fewer events (online-only Data Supplement Figures XIV–XXIX). The inverse association of systolic blood pressure during the first 5 years of follow-up was somewhat more prominent compared with total follow-up, especially for provoked VTE.

Discussion

This meta-analysis of 244 865 participants and 4910 VTE events from 9 prospective studies demonstrated that, other than the association of smoking with provoked VTE, the modifiable traditional CVD risk factors (ie, hypertension, hyperlipidemia, diabetes, and smoking) were not independently associated with overall or subtypes of VTE. Although hypertensive status was not associated with VTE, higher systolic blood pressure was associated with a decreased risk of VTE, which was more obvious for unprovoked versus provoked VTE and for PE versus DVT. Continuously modeled lipid measures and glucose showed no meaningful associations with overall or subtypes of VTE.

Several studies have reported on the association of CVD risk factors with VTE.6–16 Because of inconsistent results, no agreement was reached on whether traditional CVD risk factors are associated with incident VTE. This meta-analysis of individual participant-level data of high-quality prospective studies is the first on this topic. All included cohort studies had the maximum score on the Newcastle-Ottawa Quality Assessment Scale of Cohort Studies. Aggregated-level data meta-analyses have been published on the association of hypertension (n=1), hyperlipidemia (n=1), diabetes mellitus (n=4), and smoking (n=2) with VTE.8–12 Because of differences in definitions, study designs, covariates considered, inclusion of nonvalidated VTE events, and inability to differentiate among VTE subtypes, the results of these meta-analyses are difficult to interpret. A meta-analysis by Ageno et al8 found positive associations with VTE for hypertension, hyperlipidemia, diabetes mellitus, and smoking. However, this meta-analysis did not adjust for important confounders such as age and BMI, which were confirmed to have a large impact on the results in our analyses. Meta-analyses on the associations of diabetes mellitus and smoking with VTE largely share the same limitations.9–12 Consistent with our findings, Bell et al11 reported that the association of diabetes mellitus was not significant once the estimates were adjusted for age, sex, and BMI.

Cheng et al12 performed an extensive aggregated-level data meta-analysis for associations of both former and current smoking with VTE and showed statistically significant associations (relative risks of 1.26 [95% CI: 1.16–1.37] for current and 1.07 [95% CI: 1.04–1.11] for former smoking in the cohort studies). In our VTE subtype analyses, the association of smoking with provoked VTE (fully adjusted HR=1.36 and 1.11 for current and former smoking, respectively) and the association of former smoking with unprovoked VTE were similar to the observation of Cheng et al, 12 but we observed no association between current smoking and unprovoked VTE that they observed (relative risk of 1.28 [95% CI: 1.16–1.42]). However, besides adjustment for different sets of covariates across the included studies and inclusion of nonvalidated VTE events, the number of studies contributing to each analysis differed across VTE subtypes in the meta-analysis by Cheng et al, 12 which complicates interpretations. The stronger association between smoking and provoked VTE in our meta-analysis could be explained by the well-known association between smoking and cancer and the increased risk of hospitalization for respiratory illnesses, myocardial infarction, and stroke causing immobilization. This speculation is supported by the results of the Iowa Women’s Health Study and the Tromsø study.26,27 The latter study showed that the apparent association between smoking and provoked VTE disappeared in cause-specific analyses where individuals were censored at the occurrence of first cancer or myocardial infarction.27

In the current meta-analysis, continuous blood pressure measures, in particular systolic blood pressure, showed an inverse association with VTE risk. One previous study, which is included in our meta-analysis, also found an inverse association between blood pressure and VTE.28 Exclusion of this study did not alter the associations (data not shown). It is possible that the inverse association was caused by the competing risk of comorbid conditions such as atrial fibrillation, which is strongly associated with high blood pressure, with subsequent anticoagulant drug use being protective against VTE. Moreover, some antithrombotic effects have been described for antihypertensive drugs such as the angiotensin converting enzyme inhibitors.29

Our meta-analysis has some limitations. Although care was taken to harmonize the definitions across studies, some differences remained, such as differences in assays and blood pressure measurement devices. Definitions of provoked VTE varied to some extent across studies, as listed in the online-only Data Supplement. However, little evidence was found for heterogeneity across studies. Some experts consider a 1-stage meta-analysis of individual participant data as the best method of evidence synthesis. However, in the setting of the same prespecified definitions and cutoff values across all studies, the 2-stage method of individual participant data provides the same estimates as the 1-stage method.30 Information on the use of anticoagulant and antithrombotic drugs at baseline and during follow-up was not available in most studies. Results of the current meta-analysis may not be generalizable to non-white populations given that in most studies primarily white individuals were enrolled. In general, a long-term follow-up without repeated measures may introduce regression dilution bias; however, in our analyses, it seems unlikely given that the results were similar in the sensitivity analyses of limiting follow-up to the first 5 years. Finally, the results of particularly the continuous analyses should be interpreted in light of clinical significance; because of high statistical power, small and clinically irrelevant associations were sometimes statistically significant (eg, normal range of lipid measures and unprovoked VTE or normal range of glucose levels and overall/subtypes of VTE). Despite these limitations, this individual participant data meta-analysis provides conclusive evidence on the association between CVD risk factors and VTE.

In conclusion, in this individual-level data meta-analysis of prospective studies with measured CVD risk factors in ≈250 000 participants and ≈5000 validated VTE events, the modifiable traditional CVD risk factors were not associated with increased risk of VTE, with the exception of the association between cigarette smoking and provoked VTE. Our findings suggest that previously reported positive associations between traditional CVD risk factors and VTE are likely caused by not accounting for confounding factors.

Acknowledgments

Drs Mahmoodi, Cushman, and Zakai conceived the study concept and design. Dr Mahmoodi developed the statistical code, which was shared with the collaborating studies. Analyses of individual studies were performed by the representing coauthor using the same centrally developed code. Dr Mahmoodi meta-analyzed the estimates. All authors took part in the interpretation of the data. Drs Mahmoodi, Cushman, and Zakai drafted the manuscript, and all authors provided critical revisions of the manuscript for important intellectual content. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services.

Sources of Funding

Individual studies were supported by a variety of sources for enrollment and data collection, including laboratory measurements and follow-up (online-only Data Supplement). The current meta-analysis was sponsored by a small grant (<$10 000) provided by the Sint Antonius Hospital’s research fund. The sponsors had no role in the study design, analysis, data interpretation, or writing of the article. Dr Mahmoodi had full access to the output and estimates of the studies and performed the meta-analysis of the estimates; individual-level data were accessible by the representing coauthor of the individual studies. All authors had final responsibility for the decision to submit for publication.

; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation. 2014;129(25 Suppl 2):S49–S73. doi: 10.1161/01.cir.0000437741.48606.98.

Clinical Perspective

What Is New?

This first individual-level data meta-analyses of prospective studies demonstrates that traditional cardiovascular risk factors are not independent risk factors for venous thromboembolism (VTE).

Cigarette smoking, in particular current smoking, was associated with mildly elevated risk of provoked VTE, which may be mediated through comorbid conditions such as cancer.

Higher systolic blood pressure showed an inverse association with VTE risk, which may be caused by competing risk of comorbid conditions such as atrial fibrillation, which is strongly associated with high blood pressure, with subsequent anticoagulant drug use being protective against VTE.

What Are the Clinical Implications?

Traditional risk factors for venous and arterial disease differ, supporting different pathogenesis of these thrombotic disorders.

Traditional cardiovascular disease risk factors should not be used to assess risk of (first) VTE.